PROJECT SUMMARY The unusually high metastatic proclivity of pancreas cancer is life-limiting for a majority of patients including those diagnosed at early stages. A minority of patients nevertheless present with and succumb to locally destructive disease. These distinct disease presentations and predilections for distant spread versus primary tumor growth also suggest that the appropriate application of systemic versus local therapies might increase their efficacy and prolong survival, even as we await the development of more effective targeted therapies. We have undertaken a systematic effort to dissect the pathophysiologic mechanisms underlying the extreme lethality of pancreatic ductal adenocarcinoma (PDA) primarily through the generation and study of genetically engineered mouse models (GEMMs) of the disease that faithfully recapitulate the clinical syndrome, histopathology, molecular features, and response and resistance to treatments seen in the human disease. We have recently developed model systems that manifest the two disease phenotypes described above and used these systems to uncover a metastatic program orchestrated by the Runx3/RUNX3 transcription factor that governs the balance between cell division and dissemination. This program slows the proliferation of tumor cells while increasing their ability to disseminate and successfully colonize distant sites. Runx3, acting in concert with point-mutant Trp53 and distinct gene dosages of Dpc4/Smad4, suppresses local growth at the expense of distant spread. In this proposal, we seek to further unravel the mechanisms underlying this decision node in pancreas cancer disease behavior and the influences that distinct combinations of tumor suppressor gene mutations can have on both the tumor epithelial cells and the metastatic niche. These aims will be accomplished through the generation and characterization of novel GEMMs of PDA; identification of the composition, target gene occupancy and transcriptional outputs of Runx3-associated transcriptional complexes; and characterization of extracellular vesicles that mediate cell behaviors promoting metastasis. Collectively, these investigations will reveal the mechanisms underlying the extraordinary competency of PDAs to metastasize, identify new potential targets to disrupt this capability, and help inform the appropriate selection of local vs. systemic treatment modalities already in use in the clinic.